Cancers are regarded as one of the most common human diseases in the world. According to the statistical data released by WHO (World Health Organization), more than 10 million people are diagnosed with cancer every year and 6 million people (representing 12% of deaths worldwide) die as a result of this deadly disease. Moreover, global cancer rates are projected to increase by 50% to 15 million by 2020. Although tremendous advances have been made in the understanding of the molecular pathology of malignant tumors, progress in the development of novel anti-cancer drugs has remained slow.
Cancer therapies attempt to exploit differences between malignant tumor cells and normal cells and often take advantage of major distinctions within cell-cycle control mechanisms. As compared to the majority of normal somatic cells that are in a quiescent phase of cell cycle, cancer cells undergo a much faster and more disorganized cell cycle. Mitosis is a stage of the cell cycle in which the microtubule system plays a crucial role. Disruption of the microtubule spindle formation either by inhibiting polymerization or preventing depolymerization of tubulin results in cell-cycle arrest and cell death. Therefore, the microtubule system of eukaryotic cells is widely regarded as a potent drug target for the development of anti-cancer therapeutic agents. The α- and β-tubulin heterodimer is the building block of microtubules and, as such, is the biochemical target for several clinically used chemotherapeutics. Tubulin binding compounds which interfere with the dynamic stability of microtubules and disrupt the formation of mitotic spindles are widely considered one of the most desirable classes of anti-cancer agents. Indeed, great commercial success has been achieved by paclitaxel, a small-molecule microtubule stabilizer.
Clinically used compounds which interfere with microtubule dynamics usually bind to one of three major binding sites named after representative inhibitory ligands: taxane, vinca alkaloid, and colchicines. However, these clinically used anti-tubulin drugs often face limitations such as neural and systemic toxicity, poor water solubility and bioavailability, and complex synthetic pathways and isolation procedures. Moreover, these clinically-used antimitotic drugs suffer from negative side effects such as the development of peripheral neurotoxicity and the induction of various drug resistance mechanisms. For example, P-gP (P-glucoprotein) and MRP (Multidrug Resistance Protein) are both efflux pumps that expel foreign toxicants from cells to reduce or even eliminate cytotoxicity as a result of decreased intracellular drug concentrations. Furthermore, existing chemotherapeutic agents have complex synthetic pathways and are often difficult to isolate.
Colchicine was one of the first natural anti-mitotic drugs to be investigated. It binds to a single site in β-tubulin and destroys mitotic spindle formation by inhibiting tubulin polymerization. However, colchicine treatment results in high cytotoxicity and multiple side effects.
Combretastatin A-4 (CA-4) is a potent tubulin polymerization inhibitor with one of the simplest chemical structures. It has a broad spectrum of activity. Moreover, it cannot be recognized by the multidrug resistance (MDR) pump. Association with the MDR results in drug resistance as drugs and other foreign molecules are rapidly ejected from the cytoplasm. CA-4 has also been reported to inhibit tumor growth by disrupting angiogenesis. Unfortunately, the structural instability of the cis-double bond of CA-4 has limited the compound's in vivo efficacy.
Therefore, a need exists for novel anti-mitotic compounds that exhibit fewer side effects, have higher anti-tubulin activity, and which are easily synthesized and isolated.